Potentiated sulfonamide injectable preparation

ABSTRACT

Potentiated sulfonamide compositions useful for intramuscular injection are disclosed which comprise mixtures of alkali metal sulfonamides with microcrystalline potentiators wherein the microcrystals have been coated with mixtures of phospholipids and non-ionic surfactants. The compositions are advantageous in that they can be used extemporaneously by addition of sterile water for injection, the resulting aqueous preparation is stable for long periods of time and upon use the compositions are characterized by syringeability and lack of irritation at the injection site.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is concerned with pharmaceutical injectablepreparations comprising a potentiated sulfonamide for administration tomammals by the intramuscular route.

2. Brief Description of the Prior Art

The treatment of bacterial infections with sulfonamides has been knownfor several decades. Although their action on each microorganism differsdue to cross resistance, a variety of these chemotherapeutic agents showsimilar potency. Their antibacterial activity is notably increased whensulfonamides are administered in combination with a potentiator agent ofthe 2,4-diaminopirimidine group (Brit. Med. J. 410 (8) 1978; Postgrad.Med. J., 45 (Suppl.) 56, 1969). According to this reference variouscombinations between sulfonamides and potentiators have been developed.The combinations vary either in the chemical structure of agents or inthe proportion of sulfonamide and potentiator used in the preparation.

Several potentiated sulfonamides are described in the prior art (GermanPat. Nos.: 2.445.440; 2.538.678; 2.627.706; 2.631.780; 2.638.052; and2.818.281; Belgium Pat. No.: 851.060; Swiss Pat. No.: 544.053; ArgentinePat. Nos.: 172.760; 188.083; and 204.521). The prior art sulfonamidecompounds have the following basic chemical structure: ##STR1## where Ris substituted heterocycle, such as: pyridazine, pyrimidine, isoxazoland quinoxaline. For example, in the 4-amino-N-pyridazinylbenzenesulfonamide class there are: sulfamethoxy pyridazine and sulfaethoxypyridazine. In the class of 4-amino-N (2- or 4-pyrimidinyl) benzenesulfonamides there are: sulfadoxine, sulfadiazine, sulfadimetoxine,sulfadimidine, sulfisomidine, sulfametoxidiazine and the like.Sulfametoxazol and sulfioxazol are representative 4-amino-N-(3'- or5'-isoxazolyl) benzenesulfonamides. Another sulfonamide issulfaquinoxaline (chemically named 4-amino-N (2-quinoxalinyl)benzenesulfonamide). Sulfamoxol is representative of a 4-amino-N(2-oxazolyl) benzenesulfonamide.

Potentiators used in combination with sulfonamides may be substituted2,4-diaminopyrimidines of formula: ##STR2## wherein R₁, R₂, R₃ and R₄are each selected from hydrogen and methoxy groups. Representatives ofthe potentiators of Formula II are trimethoprim (5-3', 4',5'-trimethoxy-benzyl)-2,4-diaminopyrimidine, ormethoprim (5-(3',4'-dimethoxy -6'-methylbenzyl)-2,4-diaminopyrimidine) and diaveridine(5-3',4'-dimethoxybenzyl)-2,4-diaminopyrimidine).

The proportions of sulfonamide and potentiator used and described in theliterature, is generally in a range of 1:1 to 20:1, preferably 5:1 (thatis, 5 parts in weight of sulfonamide and 1 part in weight ofpotentiator).

Although the combination of sulfonamide and potentiator is morefrequently used by oral route, several injectable preparations (whichare able to give an antibacterial action faster than that obtained withtablets, capsules or suspensions) were previously known. During thedevelopment of the known injectable pharmaceutical preparationscontaining sulfonamides and their potentiator, several problems arose.According to the patent literature only a few of these problems weresolved. For example, it is a very well known fact that sulfonamides aresolubilized in water by the addition of pharmaceutically acceptableinorganic bases, such as sodium hydroxide, ammonium hydroxide or organicbases, such as triethanolamine, diethanolamine, monoethanolamine,meglumine and the like. However, potentiators such as those of the2,4-diaminopyrimidine class (which have basic characteristics) aresoluble in water only when they are salifyied with certain acids. Themixture of both solutions, gives a precipitate formed of the separatecomponents. Precipitation of course impeded injectability of thepreparation.

Another problem in the preparation of this kind of injectableformulation concerns its pH. When sulfonamides and potentiators are putinto water at a pH near to 7, they may react giving an insoluble complexformed by one mole of sulfonamide and one mole of potentiator (seeJapanese Patent No.: 73013511). To solve this problem, someinvestigators have followed two different courses. In the first coursethe components are first dissolved in water-miscible organic solvents,such as dimethylacetamide, ethanol, propyleneglycol, low molecularweight polyethyleneglycols and the like. In the second course, thesulfonamide is dissolved in water by the addition of bases, such assodium hydroxide or diethanolamine and the potentiator, inmicrocrystalline form, is suspended in the solution. In the first case,that is, when water-miscible organic solvents are used, the resultinginjectable preparations exhibit poor stability and provoke a high degreeof irritation at the injection site. In some cases, irreversible tissuenecrosis may occur. Several examples of these unstable, irritatingpreparations are known. For example, an injectable compositioncontaining sodium sulfonamide and trimethoprim dissolved in a mediumformed by polyethyleneglycol 400, ethanol, dimethylacetamide,diethanolamine and water is described in French Pat. No.: 1.523.606.Also, sulfonamide and trimethoprim have been dissolved in a mixture ofwater and dimethylacetamide (German Pat. No.: 2.445.400). In anotherinjectable preparation (described in German Pat. No.: 2.538.678)sulfonamide and 2,4-diaminepyrimidine type potentiator are dissolved ina mixture of polyethyleneglycol, ethanol, citric acid, sodium hydroxydeand water. Other injectable solutions containing sulfonamide,trimethoprim, ethanol, propyleneglycol, polyvinylpyrrolidone and waterare described in German Pat. Nos.: 2.631.779 and 2.631.780. Alsorepresentative of this state of the art is the disclosure found in U.S.Pat. No. 4,031,214.

Injectable suspensions of the prior art have the same stability problemsassociated with the solutions. They also pose other problems. Forexample, microcrystalline particles in suspension tend to formaggregates which precipitate in the bottom of vials and grow over aperiod of time. Consequently, the suspensions may not flow throughneedles commonly used for injections. The physical stability of thesesuspensions may be improved by adding certain vehicles which increasetheir viscosity. However, the increase of viscosity lowerssyringeability. Another problem commonly observed in solutions as wellas in suspensions, is the formation of small crystals of asulfonamide-potentiator complex. The low diffusion of such a preparationat the injection site and the high pH (typically greater than 10),provoke local irritation and even irreversible necrosis (see Rasmussen,F.; Svensen, O.: Res. Vet. Sci., 20, 50 (1) 1976).

The present invention is of a potentiated sulfonamide preparation forinjection, possessing greater stability than the prior art preparations,without the aforementioned problems. The preparations of the invention,upon intramuscular administration, do not provoke irritation or causeirreversible tissue alteration at the injection site. They exhibitexcellent syringeability.

SUMMARY OF THE INVENTION

The invention comprises a pharmaceutical composition, which comprises;in admixture, (a) an alkali metal sulfonamide; and (b) microcrystals ofa potentiator for such sulfonamide, said microcrystals being coated witha mixture of a phospholipid and a non-ionic surface-active agent. Thecompositions of the invention also include aqueous mixtures of theadmixtures described above, which are useful for intramuscularadministration to mammals, including humans, in need of sulfonamidetherapy.

The invention also comprises the method of preparing the compositions ofthe invention and their use in treating mammals, including humans, fordiseases responsive to sulfonamide treatment.

The term "microcrystal" as used herein means a crystal having a particlesize (average diameter) within the range of from about 2μ to about 40μ.

DETAILED DESCRIPTION OF THE INVENTION

Any of the previously known, pharmaceutically acceptable sulfonamidesmay be used in the method of the present invention and as ingredients ofthe compositions of the invention. The sulfonamides used in thecompositions of the invention are preferably salified with an alkalimetal, preferably sodium, prepared following known methods of synthesis.Generally they are obtained by dissolving sulfonamide in an alcoholicmedium, adding an alkali hydroxide alcoholic solution, and precipitatingthe insoluble salt. The use of preformed sulfonamide alkaline saltsinstead of preparing them in situ in the final pharmaceutical productavoids an alkali excess in the final product. An alkali excess increasesthe potential for tissue injury at the injection site when the finalproduct is used.

The potentiator component of the compositions of the inventionpreferably belonging to the 2,4-diaminepyrimidine class of compounds maybe prepared by dissolving the potentiators in a water-alcohol medium andthen precipitating it in microcrystalline form by the addition of anaqueous solution of a non-ionic surfactant and a phospholipid. In thisway, potentiator microcrystals which have a size suitable to avoidsyringeability problems are obtained, coated with surfactant andphospholipid. The coating on the microcrystals results in a stablesuspension of the microcrystals in sterile water, without the aid of anysuspending agent which might provoke not only a greater irritation atthe injection site, but a lower chemotherapeutic diffusion in tissuesand a decrease in injectability. This coating also prevents themicrocrystal aggregation problems of the prior art. The good diffusionof this preparation in tissues is believed to be related to the coatingof the microcrystals as described herein and improves syringeability ofthe compositions.

The non-ionic surface-active agents (surfactants) employed in the methodof the invention is not critical as long as the one selected ispharmaceutically acceptable. Such surfactants are well known as is theirpreparation. Representative of such surfactants are thepolyoxyalkylenesorbitan esters of fatty acids having 12-18 carbon atoms(with saturation or non-saturation of the hydrocarbon chain). Examplesof such esters are the monooleates, monolaurates, monopalmitates andmonostearates of polyoxyethylene sorbitan. Preferred are themonostearates and monopalmitates of polyoxyethylene sorbitan.

The particular phospholipid employed in the method of the invention isalso not critical as long as it is pharmaceutically acceptable.Representative of such phospholipids are phosphatidylcholine, bothnaturally occurring and synthetically prepared, phosphatidic acid,lysophosphatidylcholine, phosphatidylserine, phosphatidylethanolamine,sphingolipids, phosphatidyglycerol, spingomyelin, cardiolipin,glycolipids, gangliosides, cerebrosides and the like used eithersingularly or intermixed such as in soybean phospholipids. Preferred arethe phospholipids of the lecithin type, most preferably soy-beanlecithin.

The method of the invention for preparing the compositions of theinvention may be carried out by coating microcrystals of the potentiatorcompound with the surfactant and phospholipid and then admixing thecoated microcrystals with the sulfonamide.

Advantageously, the microcrystals of potentiator are formedsimultaneously with the coating thereof. This is carried out by formingthe microcrystals from an aqueous solution of potentiator compound inthe presence of the non-ionic surfactant and the phospholipid asdescribed above. As the microcrystals precipitate, they are coated withthe surfactant and the phospholipid.

The ratio of proportions between surfactant and phospholipid may vary ina range of 1:30 to 1:70. A 1:50 ratio; that is, 1 part of phospholipidand 50 parts of surfactant is preferably used. The proportion ratiobetween potentiator:phospholipid:surfactant depends on the volume of thesystem and may vary between 100:1:30 and 300:1:70. Using a system of 1part of ethanol to two parts of water, advantageous yields have beenobtained. The proportions or ratio of sulfonamide to coated potentiatormay be any of the proportions previously known and used for potentiatedsulfonamide compositions.

The sterilization of solid compositions of the invention, i.e.; mixturesof sulfonamide alkali salt and coated potentiator may be carried outwith ethylene oxide, which does not modify any physico-chemical propertyof the desired composition. The extemporaneous preparation of theinjectable mixture with addition of sterile water for injection, bringsa soluble sulfonamide alkali salt together with thesurfactant-phospholipid coated potentiator micro crystals, in a systemwhere the pH is in an advantageous range of 8.5-9.5. This is a pH lowerthan those found in previously known suspensions and is suitable toavoid the formation of undesired complexes. Furthermore, anextemporaneous pharmaceutical composition prepared by the method of thepresent invention has improved stability. The injection of this newpotentiated sulfonamide injectable composition in mammals is perfectlytolerated and it provokes neither irritation nor local irreversiblenecrosis. The latter is probably due to the very small surfactant andphospholipid presence (less than 0.1%) which coat microcrystals in thecompositions of the invention. The very small surfactant presence avoidsfoam formation which is generally found in injectable preparationscontaining higher amounts of surfactant. The high syringeability of thecompositions of the invention, that is the ease with which thepreparation flows through hypodermic needles, is another of itsadvantageous properties. This high syringeability is due in part to itslow viscosity and because it is an aqueous suspension without thepresence of any suspending agent or any other pharmaceutical aid. Thecoated microcrystals also resist aggregation.

One of the main advantages of this invention, is the low irritability ofthe injection site following injection of the compositions of theinvention. Thus, while previously known injectable preparations provokeirritation at the injection site, even reaching irreversible necrosis,the pharmaceutical compositions herein described are less irritating.

Thus, using the process of the invention to obtain the new potentiatedsulfonamide injectable compositions of the invention, that is thesimultaneous coating and microcrystallization of potentiator, itsmixture with the corresponding sodium sulfonamide and sterilization;gives new extemporaneous compositions. Their reconstitution, that is theaddition of sterile water before use, provides a stable suspensioncharacterized by a pH range of 8.5-9.5, good syringeability and lowirritation at the injection site when administered to mammals.

The invention will be more fully explained in the following examples,which should not be considered as limiting the invention.

EXAMPLE I

39.4 g (0.156 moles) of sulfamethoxazol were suspended in 490 ml ofisopropanol and then heated to 60° C. In a separate vessel a 1 N sodiumhydroxide methanolic solution was prepared. 158 ml of the lattersolution was heated and added to the suspension, with continuousstirring. After a few minutes the system became a solution, and then thesalt began to precipitate. The reaction medium was cooled to 0°-5° C.and maintained at this temperature for two hours, the precipitate wasfiltered and washed with isopropanol (3×20 ml). The solid was dried at40° C. for 10 hours under vacuum to obtain 33 g (Yield: 75.0%) of sodiumsulfamethoxazol (p.m.p. 288°-290° C.; titrimetric assay 99.3%).

EXAMPLE II

9 g of sodium hydroxide were dissolved in 250 ml of methanol. Intoanother suitable container a suspension of sulfaquinoxaline inisopropanol was prepared (45 g; 0.15 moles, in 470 ml). The suspensionwas heated to a temperature of 40°-45° C., and the sodium hydroxidemethanolic solution was added, with continuous stirring. After thecomplete dissolution of the suspended sulfaquinoxaline was achieved, asalt began to precipitate. The system was allowed to reach roomtemperature, maintaining continuous stirring, over a period of 3 hours.The precipitate was filtered, washed with isopropanol (3×30 ml) anddried, under vacuum at 40° C. to obtain 32.9 g (Yield: 68.1%) of sodiumsulfaquinoxaline (m.p. over 300° C.; titrimetric assay 99.7%).

EXAMPLES III TO X

Following the general procedure described in Examples I and II, supra.,but replacing the sulfonamides as used therein with other sulfonamides,the following sodium sulfonamides were prepared:

    ______________________________________                                                            YIELD      ASSAY                                          COMPOUNDS           %          %                                              ______________________________________                                        Sodium Sulfamethoxypyridazine                                                                     59.4       99.4                                           Sodium Sulfaethoxypyridazine                                                                      65.2       99.8                                           Sodium Sulfadoxine  74.3       99.4                                           Sodium Sulfadiazine 85.1       100.9                                          Sodium Sulfametazone                                                                              73.0       100.4                                          Sodium Sulfisomidine                                                                              75.2       99.8                                           Sodium Sulfamethoxydiazine                                                                        68.4       100.6                                          Sodium Sulfamoxol   76.6       100.2                                          ______________________________________                                    

EXAMPLE XI

Sorbitan monostearate polyoxyethylene (30 g) and soybean lecithin (0.6g) were dissolved in demineralized water (2000 ml), with stirring at atemperature of 40° C. In a separate beaker a solution of trimethoprim,consisting of 60 g of trimethoprim in a solvent mixture of ethanol (600ml) and water (300 ml), was prepared. The solution of trimethoprim wasfiltered and added to the first stirred solution, heated to 40° C. Theresulting mixture was then cooled to a temperature of 0°-5° C., andafter 2 hours the solid was filtered and then dried at 40° C. To obtainmicrocrystalline trimethoprim (50 g; Yield: 83.3%) coated withsurfactant and lecithin.

EXAMPLE XII

1850 ml of an aqueous solution containing soybean lecithin (0.04%) andsorbitan monopalmitate polyoxyethylene (2%), was prepared. In anotherbeaker, 60 g of diaverdine was dissolved in a solvent system ofethanol-isopropanol-ethyl acetate-water (50:10:5:35). The two solutionswere heated to 40°-45° C., and then the diaverdine solution was slowlyadded into the first solution, with continuous stirring. The resultingmicrocrystalline suspension was cooled to a temperature of 15°-10° C.,filtered and dried at 40° C., under vacuum to obtain 53 g (Yield: 88.3%)of microcrystalline diaveridine coated with surfactant and lecithin.

EXAMPLE XIII

Following the general procedure described in Example XI, supra.,microcrystalline ormethoprim coated with surfactant and lecithin (Yield:87.4%) was obtained.

EXAMPLE XIV

Sodium sulfamethoxazol (2.174 kg) obtained according to Example I, andmicrocrystalline trimethoprim (400 g) obtained according to Example XI,were poured into a stainless cylindrical tank mixer. The ingredientswere mixed until an uniform powder was obtained and the powder wassterilized with ethylene oxide for 5 hours. The sterile mixture wasfractionated into 10 ml vials (performing this operation in a cleanroom, class 100). Each vial contains 515 mg.

EXAMPLES XV TO XIX

Following the general procedure of Example XIV, supra., the followingpharmaceutical preparations were prepared:

    __________________________________________________________________________                                            ACID SULFONAMIDE:                            ACTIVE INGREDIENTS      AMOUNT PER                                                                             POTENTIATOR                           EXAMPLE                                                                              SODIUM SULFONAMIDE                                                                           POTENTIATOR                                                                            VIAL (mg)                                                                              PROPORTION                            __________________________________________________________________________    XV     Sulfamoxol     Trimethoprim                                                                           480.sup.○1                                                                 (513).sup.○2                                                                5:1                                   XVI    Sulfaquinoxaline                                                                             Diaveridine                                                                            200 (212)                                                                              4:1                                   XVII   Sulfadimethoxine                                                                             Trimethoprim                                                                           480 (508)                                                                              5:1                                   XVIII  Sulfadoxine    Ormethoprim                                                                            400 (425)                                                                              7:1                                   XIX    Sulfisoxazol   Ormethoprim                                                                            450 (483)                                                                              7:2                                   __________________________________________________________________________     .sup.○1   Weight expressed as acid sulfonamide + potentiator           .sup.○2   Actual weight                                           

SYRINGEABILITY TEST

To the injectable preparations obtained in Examples XIV to XIX, 5 mldistilled water was added, and the pH and sedimentation times weremeasured. The results are shown in the following table. Using separatevials of the preparations obtained in Examples XIV to XIX, and using a10 ml hypodermic syringe with a 20 gauge's needle, 5 ml of distilledwater were poured into each vial. Each vial was gently shook for 30seconds. Using the same syringe and needle, 5 ml of air was injectedinto each vial and the injectable suspension was allowed to fill thesyringe. Each test was carried out with 10 vials, observing whether thesuspension flows freely into the syringe or not. The test results areshown in the following table.

    ______________________________________                                                                  SEDI-                                                                         MEN-                                                                          TA-     SYRINGE-                                                              TION    ABILITY                                                               TIME    N° of assays/                                                  (min-   observed                                    ACTIVE INGREDIENTS*                                                                             pH      utes)   obstructions.                               ______________________________________                                        Sulfamoxol-Trimethoprim                                                                         8.9-9.1 19      10/1                                        Sulfaquinoxaline-diaveridine                                                                    8.6-8.8 27      10/0                                        Sulfadimethoxine-Trimethoprim                                                                   8.7-9.0 20      10/0                                        Sulfadoxine-Ormethoprim                                                                         9.1-9.3 17      10/1                                        Sulfisoxazol-Ormethoprim                                                                        9.0-9.2 31      10/0                                        Sulfamethoxazol-Trimethoprim                                                                    9.0-9.2 25      10/0                                        ______________________________________                                         *Sodium sulfonamides.                                                    

PHARMACOLOGICAL TESTS (Irritability Evaluation)

The pharmaceutical preparations obtained according to Examples XIV toXIX, supra., were reconstituted with 5 ml of sterile water forinjection. Their irritability, that is the muscular damage caused bytheir intramuscular administration, at the injection site was evaluated,using two animal species:

A--RABBITS: Shintain, S. et. al. method (Toxicol. and Appl.Pharmacology, 11, 293-301, 1967) was applied. Male albino rabbitsweighing 2.5-3.5 kg were used. Reconstituted preparations wereadministered by intramuscular route. The procedure was repeated dailyfor 4 days using the same injection site. After the 4 days, the rabbitwas sacrificed, the muscle was dissected and local tissue irritation wasgrossly scored from 0 to 5 according to the following criteria: score0+no discernible gross reaction; score 1+slight hyperemia anddiscoloration; score 2=moderate hyperemia and discoloration; score3=distinct discoloration in comparison with the color of the surroundingarea; score 4=brown degeneration with small necrosis; score 5=widespreadnecrosis with an occasionally abscess of the muscle. The irritation wasgraded using the following categories: "none" for 0.4 or less; "slight"for 0.5-1.4; "mild" for 1.5-2.4; "moderate" for 2.5-3.4; "marked" for3.5-4.4 and "severe" for 4.5 or more. Results of the evaluation were thefollowing:

    ______________________________________                                        PHARMACEUTIC COMPOSITION                                                                     PRO-                                                                          POR-  EVALUATION                                               *ACTIVE INGREDIENTS                                                                            TION    SCORE    CATEGORY                                    ______________________________________                                        Sulfamethoxazol-Trimethoprim                                                                   5:1     2.33     mild                                        Sulfisoxazol-Ormethoprim                                                                       7:2     2.94     moderate                                    Sulfadimethoxine-Trimethoprim                                                                  5:1     1.66     mild                                        Sulfamoxol-Trimethoprim                                                                        5:1     1.38     mild                                        Sulfaquinoxaline-Diaveridine                                                                   4:1     1.67     mild                                        Sulfadoxine-Ormethoprim                                                                        7:1     2.34     mild                                        Control (5 ml of pyrogen-free                                                                  --      0.0      none                                        saline solution)                                                              ______________________________________                                         *Sodium sulfonamides.                                                    

B--RATS: Kienel method (Arzneim. Forsch., 23, 263 (2), 1973) was used.Reconstituted preparations were administered once by intramuscularroute. After 24 hours, and during 10 days, animals were then sacrificedobserving local tissue injury and giving a score proportional to theirdiameter (Maximum injury degree has a score of 64). Results are shown inthe following table:

    __________________________________________________________________________    PHARMACEUTICAL COMPOSITION                                                                           EVALUATION                                             *ACTIVE INGREDIENTS                                                                          PROPORTION                                                                            SCORE                                                                              OBSERVATIONS                                      __________________________________________________________________________    Sulfadimethoxine-Trimethoprim                                                                5:1     35   Good muscular regeneration                        Sulfadoxine-Ormethoprim                                                                      7:1     42   Good muscular regeneration                        Sulfisoxazol-Ormethoprim                                                                     7:2     41   Good muscular regeneration                        Sulfamethoxazol-Trimethoprim                                                                 5:1     33   Very good muscular reg.                           Sulfaquinoxaline-Diaveridine                                                                 4:1     42   Moderate muscular reg.                            Sulfamoxol-Trimethoprim                                                                      5:1     38   Good muscular regeneration                        Control (5 ml of pyrogen-free                                                                --      12   Without muscular injury                           saline solution)                                                              __________________________________________________________________________

What is claimed:
 1. A pharmaceutical composition, which comprises;inadmixture, (a) from 1 to 20 parts by weight of an alkali metalsulfonamide, said sulfonamide having the structural formula: ##STR3##wherein R is selected from the group consisting of6-methoxy-3-pyridazinyl, 6-ethoxy-3-pyridazinyl,5,6-dimethoxy-4-pyrimidinyl, 2,6-dimethoxy-4-pyrimidinyl,2,6-dimethyl-4-pyrimidinyl, 2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl,5-methoxy-2-pyrimidinyl, 3,4-dimethyl-5-isoxazolyl,5-methyl-3-isoxazolyl, 4,5-dimethyl-2-oxazolyl and 2-quinoxalinyl; and(b) one part by weight of microcrystals of a potentiator for saidsulfonamide, said potentiator being a 5-substituted2,4-diaminopyrimidine of the formula: ##STR4## wherein R₁ is selectedfrom the group consisting of 3,4,5-trimethoxybenzyl,3,4-dimethoxy-6-methylbenzyl and 3,4-dimethoxybenzyl groups, saidmicrocrystals being coated with a mixture of a phospholipid selectedfrom the group consisting of phosphatidylcholine, both naturallyoccurring and synthetically prepared, phosphatidic acid,lysophosphatidylcholine, phosphatidylserine, phosphatidylethanolamine,sphingolipid, phosphatidylglycerol, spingomyelin, cardiolipin,glycolipid, ganglioside, cerebrosides and lecithin; and a non-ionicsurface-active agent; the proportion ratio betweenpotentiator:phospholipid:surfactant being between 100:1:30 and 300:1:70.2. The composition of claim 1 wherein said alkali metal is sodium. 3.The composition of claim 1 wherein the phospholipid is a lecithin. 4.The composition of claim 1 wherein the non-ionic surface-active agent isselected from the class consisting of monostearates and monopalmitatesof polyoxyethylene sorbitan.
 5. The composition of claim 1 which furthercomprises water for injection, said composition having a pH within therange of 8.5 to 9.5.
 6. The composition of claim 1 wherein thesulfonamide is sulfadimethoxine and the potentiator is trimethoprim.